WO2011140608A1 - Neuropsychopharmacological treatment regimes for treating psychological disorders - Google Patents

Abstract

Neuropsychopharmacological treatment regimes are provided for treating a range of psychological disorders including depression and their sub-threshold forms. A number of treatment protocols are disclosed, comprising a synergistic combination of oxytocin and oestrogen which target the hypothalamopituitary adrenal axis, in combination with antidepressant agents. These treatment protocols may be used alone or in combination with other behavioural modification therapies, for the treatment of psychological disorders such as depression and symptoms of depression. Compositions, medicaments and agents comprising combinations of oxytocin, oestrogen and anti-depressants are also disclosed.

Description

_ i -

NEUROPSYCHOPHARMACOLOGICAL TREATMENT REGIMES FOR TREATING PSYCHOLOGICAL DISORDERS

FILING DATA [0001] This application is associated with Australian Patent Application Number 2010902054, filed on 14 May 2010 in the name of Charlotte Keating, the entire contents of which, are incorporated herein by reference.

FIELD

[0002] The present disclosure relates generally to neuropsychopharmacological treatment regimes for a range of psychological illnesses and their sub-threshold forms. Particularly, the present disclosure describes a combination of treatment protocols which target the stress-linked and/or reproductive-linked biological system and anti-depressant therapy. The neuropsycho-pharmacological approach may be used alone or in combination with other neuropsychobehavioral modification protocols.

BACKGROUND [0003] Bibliographic details of the publications referred to by author in this specification are collected alphabetically at the end of the description.

[0004] Reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in any country.

[0005] Psychological disorders represent a broad spectrum of conditions, which have a variety of behavioral and clinical manifestations. These manifestations extend from mild to heavily debilitating symptoms. Particular conditions such as major depression and anorexia nervosa often present co-morbidly and share similar symptoms despite having different phenotypes (Wade et al, American Journal of Psychiatry 157 (3) :469 -471 , 2000). Both illnesses frequently onset around the age of puberty. Patients have traditionally been prescribed anti-depressant drugs. However, the efficacy of these drugs has been contentious (Kaye et al., Nature Reviews Neuroscience 70:573-584, 2009). There is a gender bias in the onset of some psychiatric disorders. For example, depression is more prevalent in females, occurring twice as often (Burt and Quezada, Canadian Journal of Clinical Pharmacology 7<5(7j:e6-el4, 2009; Doris et al., Lancet 354: 1369-1375, 1999; Fava and Kendler, Neuron 25:3350-341, 2000). [0006] Major Depressive Disorder (MDD) represents a highly disabling illness with a lifetime prevalence of around 20% (Fava, Biol Psychiatry 53 (8) :649-659, 2003). The World Health Organization rates MDD as the leading cause of disability worldwide according to years lived with a disability (YLD) and is the fourth leading contributor to global burden of disease. By 2020, it is predicted to be the primary burden of disease worldwide (Murray and Lopez, Global burden of disease. A comprehensive assessment of mortality and disability from diseases, injuries and risk factors in J 990 and projected to 2020, Harvard University Press, 1996). Whilst many patients respond to treatment, up to 30-40% of patients fail to respond to multiple treatment trials (Fava, 2003 supra). These patients present with treatment resistant depression (TRD). TRD is presumed when at least two trials of anti-depressants from different classes fail to produce significant improvements (Berlim and Turecki, Can J Psychiatry 52(7 :46-54, 2007; Ananth, Psych Psychos 67(2):6\ -70, 1998; Rush et al, Biol Psychiatry 53 (¾ : 743 -753, 2003; Keller, J Clin Psychiatry 66(8):5-\ 2, 2005). Without successful treatment, patients remain severely disabled, have little hope of recovery and suffer one of the highest risks of suicide and mortality of any psychiatric condition (Fava, 2003 supra).

[0007] There are several subtypes of MDD (Berlim and Turecki, 2007 supra; Gold and Chrousos, Mol Psychiatry 7 3):254-275, 2002; Parker, Acta Psychiatr Scand Suppl 433:21- 30, 2007; Parker, British Journal of Psychiatry 194Λ -3, 2009). This heterogeneity may influence treatment response (Fava, 2003 supra; Komstein and Schneider, J Coin Psychiatry 62(16) :\ %-25, 2001 : Parker, 2009 supra). Subtypes include patients presenting with melancholic or non-melancholic depression. Melancholic depression is associated with greater cognitive processing abnormalities (concentration) and motor impairments, including retardation and agitation affecting the face, speech and body {Melancholic Depression, retrieved online: The Black Dog Institute, 2005). The etiology of major depression has been explained in large part by the 5-hydroxytryptamine (5-HT) hypothesis. This hypothesis proposes that the illness is initially underscored by reduced availability of synaptic 5-HT or decreased activity of the 5-HT system (Biller and Montigny, Neuropsychopharmacology 27:91s-98s, 1999; Lesch and Heils, International Journal of Neuropsychopharmacology 3: 67-79, 2000; Venstra-VanderWeele el al, .European Journal of Pharmacology 70:165-181, 2000). In addition to the 5-HT system, depressive episodes have been linked to other neurochemical and neurohormonal abnormalities, which includes the stress system, and consistent with this, pathophysiological studies have revealed dysfunction in various end-points of the hypothalamopituitary adrenal (HPA)-axis, including changes (elevations) in Cortisol levels (Gold and Chrousos, 2002 supra). Abnormalities in the HPA-axis are present in up to 80% of patients, with most reporting hyperactivity of the axis. Abnormalities in the stress system have been shown to normalize following treatment and may predict relapse-risk in patients with depression (Schule Journal ofNeuroendocrinolog 79:213-226, 2006).·

[0008] Both abnormal activity of the HPA-axis (Young et al, Psychoneuroendocrinology 29(9): 1 198-1204, 2004) and treatment resistance (Malhi et al, Acta Psych Scan 72^:302-309, 2005) are more often reported in patients with melancholic (relative to non-melancholic) symptoms of MDD. Importantly, interactions between the serotonin and HPA-axis systems may influence treatment response in MDD. For example, normalization of the HPA-axis is considered contingent for a response to anti-depressants in some patients (Binder et al, Psychoneuroendocrinology 34(I):99- W9, 2009; Young et al. 2004 supra; Juruena et al, Br J Psychiatry I94(4):342-349, 2009). In general, abnormalities reported include reduced circulating serotonin concentrations 5-HT (Meltzer and Maes, The Serotonin Hypothesis in Major Depression. In: Bloom, Kupfer (eds) Neuropsychopharmacology - 4^th Generation of Progress, The American College of Neuropsycholpharmacology, 2010), logically consistent with the therapeutic actions of SSRIs (and other anti-depressants) which bring about increased serotonin to remit symptoms. Abnormal activity of the HPA-axis is also well established (Thomson and Craighead, Neurochem Res 33(4):69\-101 , 2008; Gold and Chrousos, 2002 supra; Cyranowski et al.. Psychosomatic Medicine 70:967-975, 2008; Nemeroff and Vale, J Clin Psychiatry 66(7):5-\3, 2005).

[0009] These studies suggest potential mechanisms that may contribute to abnormal HPA- axis activity in patients with major depression. Hyperactivity of the HPA-axis is widely reported in the pathophysiology of the illness and its normalization has been linked to clinical response to anti-depressant drugs (at least in some males) [Binder et al., 2009 supra; Young et al, 2004 supra; Juruena et al, 2009 supra]. As the majority of patients with major depression present with an over-active HPA-axis, and in some patients, overactivity of the HPA-axis precludes a response to anti-depressants, potential physiological mechanisms responsible for hyperactivity and treatment adjuncts, which aim to attenuate over-activity of the HPA-axis, require further exploration.

[0010] There is an intertwine of complex stress-linked and hormonal pathways which impact on psychological conditions and disorders. There is a need to understand the extent of this intertwine in order to develop more effective neuropsychopharmacological protocols

SUMMARY

[0011) There is a range of behavioral, and clinical manifestations within the spectrum of "psychological illness". Reference to "psychological illness" includes a "neuropsychological illness" and encompasses a neurological^ psychological and/or psychiatric condition, state, disorder or sub-threshold form thereof in which a subject exhibits a behavioral or clinical phenotype characterized by abnormalities in dopamine, serotonin and/or reproductive- or stress-linked biological systems. It is proposed herein to ameliorate symptoms of neurobiological anomalies by administering to subjects, males and females, with a psychiatric condition or who are at risk of developing same, with anorexia nervosa, bulimia nervosa, major depression, including treatment resistant depression, chronic depression, psychotic depression, melancholic depression and other depressive disorder subtypes, schizophrenia anxiety disorder subtypes and other psychiatric conditions a combination of an agent which facilitates normalization of a stress-linked biological system and an anti-depressant. This may be done alone or in combination with agents which facilitate normalization of the reproductive-linked biological system which includes the hypothalamopituitary gonadal (HPG)-axis.

[0012] Reference to the stress-linked biological system includes the HPA-axis. Agents which facilitate normalization include agents which ultimately (but not solely) result in reduced Cortisol production. Such agents include oxytocin or an agonist thereof, a corticotropin-releasing hormone (CRH) antagonist, a CRH receptor antagonist, an arginine vasopressin antagonist, a adrenocorticotropin hormone (ACTH) antagonist, glucocorticoid antagonist, an anti-psychotic and a dopamine antagonist or mood stabilizer. Reference to "anti-depressants" includes selective serotonin re-uptake inhibitors (SSRIs), selective serotonin noradrenergic re-uptake inhibitors (SSNRIs), tetra-cyclic and tri-cyclic antidepressants and a monoamine oxidase inhibitor (MAOI). Agents which facilitate normalization of the HPG-axis include estrogens as well as progestogens. [0013] The two or more drugs may be administered simultaneously or sequentially and in any order. When sequentially administered, the period of time between administration of each drug may be nanoseconds, milliseconds, seconds, a minute or minutes, hours or days. The drugs may be administered via the same or different routes.

[0014] An aspect enabled herein is a method for treating a human subject diagnosed with. symptoms of depression, the method comprising administering to the subject, effective amounts of oxytocin and estrogen for a time and under conditions sufficient to amelioratethe symptoms of depression. In an embodiment, the treatment protocol further comprises the administration of an anti-depressant such as selected from an SSRI, SSNRI, tri-cyclic anti-depressant and a tetra-cyclic anti-depressant. In an embodiment, the depression is treatment resistant depression. In an embodiment, the depression is chronic depression. In an embodiment, the depression is associated with another illness. Taught herein is a pharmaceutical composition comprising: (i) an anti-depressant such as selected from an SSRI, SSNRI, a tri-cyclic anti-depressant and a tetra-cyclic anti-depressant; (ii) oxytocin; and (iii) estrogen. Examples of an SSRI include escitalopram, sertraline, citalopram, fluoxetine and agomelatine. Examples of an SSNRI include esmertazapine, venlafaxine, desvenlafaxine and duloxetine. Examples of a tri-cyclic anti -depressant include amitriptyline and imip^'ramine. Examples of a terra-cyclic anti -depressant include amoxapine and mirtazapine. [0015] The present disclosure further contemplates a neuropsychopharmalogical medicament comprising two or more drugs selected from an agent which facilitates normalization of a stress-linked biological system and anti-depressant and anti-psychotic and mood stabilizer and reproductive linked system-modulator, for use in treating a psychological illness, phenotype, state, condition or sub-threshold form thereof.

[0016] Psychological conditions contemplated herein include depression (including major depressive disorder [MDD] and postnatal depression as well as treatment resistant depression [TRD], chronic depression, psychotic depression or melancholic depression), eating disorders (such as anorexia nervosa and bulimia nervosa), bipolar disorder, anxiety disorders, addiction, dementia, epilepsy, schizophrenia, Tourette's syndrome, obsessive compulsive disorder (OCD), panic disorder, PTSD, phobias, acute stress disorder, adjustment disorder, agoraphobia without history of panic disorder, alcohol dependence (alcoholism), amphetamine dependence, brief psychotic disorder, cannabis dependence, cocaine dependence, cyclothymic disorder, delirium, delusional disorder, dysthymic disorder, hallucinogen dependence, nicotine dependence, opioid dependence, paranoid personality disorder, Parkinson's disease, schizophrenia, schizoaffective disorder, schizoid personality disorder, schizophreniform disorder, schizotypal personality disorder, sedative dependence, shared psychotic disorder, smoking dependence and social phobia.

[0017) The drugs may be given alone or as part of another therapeutic program and/or behavioral modification therapy or counselling.

[0018] Enabled herein is the use of two or more drugs selected from an agent facilitates normalization of- a stress-linked biological system and an anti -depressant, and antipsychotic or mood stabilizer and reproductive linked system-modulator, in the manufacture of a medicament for the treatment or prophylaxis of a psychological illness, phenotype, state, condition or sub-threshold form thereof. "Prophylaxis" in this context is particularly useful in pre-emptive treatment of at risk individuals or individuals who have a genetic predisposition for psychological illness or whose lifestyle may result in psychological illness.

[0019] Aspects taught herein include a method for treating a male or female subject with a psychological illness, phenotype, state, condition or sub-threshold form thereof, the method comprising administering to the subject two or more drugs selected from an agent which facilitates normalization of a stress-linked biological system and an anti-depressant and mood stabilizer and anti-psychotic and reproductive linked system-modulator, in amounts and under conditions sufficient to ameliorate symptoms of the psychological, illness, phenotype, state, condition or sub-threshold form thereof.

[0020] Abbreviations used in the present specification are defined in Table 1. Table 1

Abbreviations

Abbreviation Definition

ACTH Adrenocorticotropin hormone

AVP Arginine vasopressin

CRH Corticotropin-releasing hormone

HPA-axis Hypothalamopituitary adrenal axis

HPG-axis Hypothalamopituitary gonadal axis

MDD Major depressive disorder

OCD Obsessive compulsive disorder

PTSD Post-traumatic stress disorder

SERM Selective estrogen receptor modulator

SSNRI Selective serotonin and noradrenergic re-uptake inhibitor

SSRI Selective serotonin re-uptake inhibitor

TRD Treatment resistant depression

B.RIEF DESCRIPTION OF THE FIGURES

[0019] Figure 1 is a schematic representation of hypothalamopituitary adrenal (HPA)-axis showing sites of proposed action of oxytocin or synthetic oxytocin agonist and CRH antagonist. Oxytocin restrains CRH and AVP neurones in the hypothalamus thus reducing synthesis and secretion of these neuropeptides, hence decreasing HPA-axis activity. The CRH antagonist blocks the actions of CRH on coriicotropes, decreasing stimulation of ACTH, ultimately reducing adrenal Cortisol production. [0020] A color photograph of Figure 1 is available from the Patentee upon request or from an appropriate Patent Office. A fee may be imposed if obtained from a Patent Office.

DET AILED DESCRIPTION

[0021] Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element or integer or method step or group of elements or integers or method steps but not the exclusion of any other element or integer or method step or group of elements or integers or method steps.

[0022] The singular forms "a", "an" and "the" include plural aspects unless the context clearly dictates otherwise. Thus, for example, reference to "a disease condition" or "a vaccine" includes a single disease condition or a single vaccine as well as two or more disease conditions or vaccines; reference to "an agent" or "an antagonist" includes a single agent or a single antagonist as well as two or more agents or antagonists; reference to "the embodiment" includes single and multiple embodiments; and so forth.

'

[0023] An empiricaly-based protocol is taught herein based on the use of a combination of agents which facilitates normalization of a stress-linked biological system, act as an antidepressant, an anti-psychotic and a reproductive linked system-modulator to treat a psychological illness.

[0024] The stress-linked biological system includes the HPA-axis. Agents which normalize the HPA-axis include agents which reduce overactivity such as any agent which reduces Cortisol production. Such agents contemplated herein include oxytocin or agonist thereof, a CRH antagonist, a CRH receptor antagonist, a AVP antagonist and an ACTH antagonist, a glucocorticoid antagonist, an anti-psychotic and a dopamine antagonist. Reference to an anti-depressant includes tetra-cyclic and tri-cyclic agents, monoaminoxidase inhibitors and SSRIs and SSNRIs. Reference to an- anti -psychotic includes dopamine antagonists. Hence, the present disclosure provides a therapeutic protocol comprising: (i) an agent which normalizes HPA-axis activity; (ii) an SSRl or SSNRI or other anti-depressant; (iii) an anti-psychotic or (iv) mood stabilizer and/or (v) a reproductive linked modulator such as estrogen an estrogen analog or agonist or a selective estrogen receptor modulator (SERM) or estrogen pro-drug, and/or (vi) a progestogen or progestogen analog or agonist, for use in treating or ameliorating the symptoms of a psychological illness or condition. A reproductive-linked biological system includes the HPG-axis.

[0025] An aspect enabled herein is a method for treating a human subject diagnosed with symptoms of depression, the method comprising administering to the subject effective amounts of oxytocin and estrogen for a time and under conditions sufficient to ameliorate the symptoms of depression. In an embodiment, the treatment protocol further comprises the administration of an anti-depressant such as selected from an SSRI, SSNRI, tri-cyclic anti-depressant and a tetra-cyclic anti-depressant. In an embodiment, the depression is treatment resistant depression. In an embodiment, the depression is chronic depression. In an embodiment, the depression is associated with another illness. Taught herein is a pharmaceutical composition comprising: (i) an anti -depressant such as selected from an SSRI, SSNRI, a tri-cyclic anti -depressant and a tetra-cyclic anti-depressant; (ii) oxytocin; and (Hi) estrogen. Examples of an SSRI include escitalopram, sertraline, citalopram, fluoxetine and agomelatine. Examples of an SSNRI include esmertazapine, venlafaxine, desvenlafaxine and duloxetine. Examples of a tri-cyclic anti-depressant include amitriptyline and imipramine. Examples of a tetra-cyclic anti-depressant include amoxapine and mirtazapine.

[0026] By "psychological illness" or "psychological condition" is meant a psychological, neurological and psychiatric condition, disorder, phenotype, state or sub-threshold form thereof in which a subject exhibits a behavioral or clinical phenotype characterized by abnormalities in the stress-linked biological system and/or reproductive-linked biological system. The term "psychological illness" or "psychological condition" encompasses all such neuropsychological and neuropsychiatric phenotypes. The present disclosure teaches a method of ameliorating the symptoms of neurobiological anomalies such as associated with major depression including major depressive disorder (MDD), treatment resistant depression, chronic depression, schizophrenia, anorexia nervosa, bulimia nervosa, anxiety disorder subtypes and other psychiatric conditions. Terms which are also applicable to these phenotypes include psychiatric, psychological and neurological illnesses. The term "illness" does not necessarily mean that a subject is medically incapacitated. Rather, it includes the full spectrum of psychological conditions, disorders, phenotypes, states or sub-threshold forms thereof which manifest in from complete debilitation to minor behavioral, physiological and/or clinical abnormalities.

[0027] Examples of psychological illnesses contemplated by the present disclosure include but are not limited to depression (including major depression and MDD postnatal depression, treatment resistant depression, chronic depression, psychotic or melancholic depression), eating disorders (such as anorexia nervosa and bulimia nervosa), bipolar disorder, anxiety disorders, addiction, dementia, epilepsy, schizophrenia, Tourette's syndrome, obsessive compulsive disorder (OCD), panic disorder, post-traumatic stress disorder (PTSD), phobias, acute stress disorder, adjustment disorder, agoraphobia without history of panic disorder, alcohol dependence (alcoholism), amphetamine dependence, brief psychotic disorder, cannabis dependence, cocaine dependence, cyclothymic disorder, delirium, delusional disorder, dysthymic disorder, hallucinogen dependence, nicotine dependence, opioid dependence, paranoid personality disorder, Parkinson's disease, schizophrenia, schizoaffective disorder, schizoid personality disorder, schizophreniform disorder, schizotypal personality disorder, sedative dependence, shared psychotic disorder, smoking dependence and social phobia.

[0028] A particular condition contemplated herein includes MDD which includes treatment resistant depression. Reference to "depression" includes "major depressive disorder" (MDD). Reference to "anxiety disorder" includes "generalized anxiety disorder". Depression may also be associated with another illness.

[0029] Hence, the present disclosure contemplates the use of a combination of agents which facilitates normalization of a stress-linked biological system and an anti-depressant or anti-psychotic and/or reproductive system modulator (ie., estrogen) in the treatment or prophylaxis or clinical or behavioral management of subjects with or at risk of developing a psychological illness. Estrogen may also be administered. It is proposed herein that the drug combinations include in one embodiment: (1) an HPA-axis-normalizing agent selected from oxytocin or an agonist thereof; a CRH antagonist; a CRH receptor antagonist; an AVP antagonist; and a ACTH antagonist, a glucocorticoid antagonist, an anti-psychotic and a dopamine antagonist: and (2) an anti-depressant selected from an SSRI, SNRI/SSNRI and other anti-depressants or mood stabilizer. Optionally, a modulator of the reproductive-linked biological system such as the HPG-axis is also provided. An example includes estrogen, or other agent inducing estrogens and pro-estrogen drugs, as well as progestogens or agents that induce progestogens. [0030J In another embodiment, particular combinations include:

(i) SSRI + oxytocin or oxytocin agonist;

(ii) SSRI + a CRH antagonist or CRH receptor antagonist or AVP antagonist or ACTH antagonist or a glucocorticoid antagonist;

(iii) SSNRI + oxytocin or oxytocin agonist; ·

(i^'v) SSNRI + a CRH antagonist or CRH receptor antagonist or AVP antagonist or ACTH antagonist or a glucocorticoid antagonist;

(v) SSRI + oxytocin or oxytocin agonist + estrogen or a SERM or an estrogen pro-drug ie., tibolone;

(vi) SSRI + a CRH antagonist or CRH receptor antagonist or AVP antagonist or ACTH antagonist or a glucocorticoid antagonist + estrogen or a SERM of an estrogen prodrug ie., tibolone;

(vii) SSNRI + oxytocin or oxytocin agonist + estrogen; and

(viii) SSNRI + a CRH antagonist or CRH receptor antagonist or AVP antagonist or ACTH antagonist or a glucocorticoid antagonist + estrogen or a SERM or an estrogen pro-drug ie., tibolone;

(ix) SSRI + oxytocin or oxytocin agonist + estrogen or a SERM or an estrogen pro-drug ie., tibolone and/or a progestogen;

(x) SSRI + a CRH antagonist or CRH receptor antagonist or AVP antagonist or ACTH antagonist or a glucocorticoid antagonist + estrogen or a SERM or an estrogen pro- drug ie., tibolone, and/or a progestogen; (vii) SSNRl + oxytocin or oxytocin agonist + estrogen a SERM or an estrogen pro-drug ie., tibolone and/or a progestogen;

(xi) SSNRl + a CRH antagonist or CRH receptor antagonist or AVP antagonist or ACTH .antagonist or a glucocorticoid antagonist + estrogen or a SERM or an estrogen pro-drug ie., tibolone, and/or a progestogen;

(xii) an anti-depressant selected from SSRI, SSNRl, a tri-cyclic anti-depressant and a tetra-cyclic anti-depressant + oxytocin + estrogen; and

(xiii) oxytocin + estrogen. [0031] Components and combinations include tri- and tetra-cyclic anti-depressants, monoamine oxidase inhibitors, antipsychotics including dopamine antagonist, mood stabilizer and estrogen (or selective estrogen receptor modulator, SERM, or estrogen prodrug) and all combinations may further include super-active agonists (or inverse agonists) of CRH or AVP or ACTH or glucocorticoids as well as super-active antagonists of oxytocin

[0032] Reference to "estrogen" includes an estrogen analog, estrogen agonist and an agent which facilitates or -promotes estrogen production as well a SERM (including but not limited to raloxifene) as well as estrogen pro-drugs (ie., tibolone) or plant-like estrogens (ie., phytoestrogen).^'

[0033] Reference to "progestogen" includes a progesterone or progestogen analog, progestogen agonist and an agent which promotes progesterone (or other precursor or derivative) production. This includes but is not limited to naturally occurring and synthetic progestogens. Reference to "a progestogen" or "an agent" includes a single progestogen or a single agent as well as two or more progestogens or agents.

[0034] The present disclosure teaches a selection of neuropsychopharmacological agents based on an understanding of the interaction these drugs have on the stress-linked biological system. The combination of drugs can, in one aspect, be considered synergistic, since the combination of the drugs has more efficacious outcomes than the use of the single drugs above. Hence, the combination is functionally synergistic.

[0035] Accordingly, an aspect taught herein contemplates a method for treating a subject, male or female, with a psychological illness, phenotype, state, condition or sub-threshold form thereof, the method comprising administering to the subject an agent which facilitates normalization of a stress-linked biological system and an anti-depressant in amounts and under conditions sufficient to ameliorate symptoms of the psychological, illness, phenotype, state, condition or sub-threshold form thereof.

|0036] Another aspect enabled herein provides a method for treating a subject with a psychological illness, phenotype, state condition or sub-threshold form thereof, the method comprising administering to the subject a drug combination selected from: (i) an HPA-axis normalizing agent selected from oxytocin or an agonist thereof, a CRH or CRH receptor antagonist, a AVP antagonist, a ACTH antagonist; a glucocorticoid antagonist, an antipsychotic and a dopamine antagonist; (ii) an SSRI, SSNRI or other anti-depressant; (ie., a tri- or tetra-cyclic anti-depressant or a monoamine oxidase inhibitor) (iv) a mood stabilizer; and optionally (iii) an estrogen, estrogen analog or estrogen agonist or a SERM , estrogen pro-drug and or (iv) a progestogen or progestogen analog or agonist.

[0037] Still another aspect described herein is directed to a method of treating a human subject diagnosed with symptoms of depression, the method comprising administering to the subject effective amounts of oxytocin and estrogen. In an embodiment, the method further comprises administering to the subject an effective amount of an anti-depressant such as selected from an SSRJ, SSNRI, a tri-cyclic anti-depressant and a tetra-cyclic antidepressant.

[0038] Examples of a "selective serotonin re-uptake inhibitor" and a selective serotonin and noradrenergic re-uptake inhibitor include citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline as well as pharmacologically acceptable derivatives, analogs, homologs and formulated forms thereof. [0039] Other serotonin inhibitors or serotonin or noradrenergic uptake inhibitors include 1 -

(2-methoxyphenyl)-4-(4-(2-phthalimido)butyl)piperazine; 2-((2-

(dimethylamino)ethyl)thio)-3-phenylquinoline; 4-(2^,-metboxyphenyl)- 1 -(2'-(N-(2"- pyridinyl)-4-iodobenzamido)ethyl)piperazine; 6-nitroquipazine; alosetron; amperozide; azasetron; bemesetron; binospirone mesylate; bufotenin; cianopramine; cinanserin; clovoxamine; clozapine; CQ 32085; cyanopindolol; cyproheptadine; deramciclane; dolasetron mesylate; dotarizine; DuP 734; EEDQ; fananserin; fenclonine; GR 1 13808; GR

127935; granisetron; iprazochrome; ketanserin; LY 53857; lysergic acid diethylamide; McN 5652; MDL 100907; metergoline; methiothepin; methysergide; mianserin; N,N- dimethyltryptamine; nafronyl; ondansetron; palonosetron; pindolol; pipamperone; pizotyline; ramosetron; renzapride; risperidone; ritanserin; sarpogrelate; SB 204070A: SB

206553; SDZ 205-557; setoperone; SR 46349B; tolfenamic acid; tropisetron; UH 301 ;

WAY 1 00135; WAY 100635; wortmannin; xylamidine; zacopride; zatosetron; ziprasidone; alaproclate; amoxapine; citalopram; clomipramine; duloxetine; femoxetine; fenfluramine; fluoxetine; fluvoxamine; indalpine; milnacipran; norfenfluramine; olanzapine; paroxetine; sertraline; trazodone; venlafaxine and zimeldine.

[0040] Selective serotonin and noradrenergic re-uptake inhibitors include psychoactive drugs which antagonize various adrenergic and serotonin receptors and include esmirtazapinej mianserin, mirtazapine, setiptiline, such agents are also referred to as "tetracyclic anti-depressants". Other anti-depressants include tricyclic anti-depressants. Such agents include serotonin and/or norepinephrine re-uptake inhibitors including amitriptyline, amitriptylinoxide, butriptyline, clomipramine, demexiptiline, desipramine, dibenzepin, dimetacrine, dosulepin/dothiepin, doxepin, imipramine, imipraminoxide, lofepramine, melitracen, metapramine, nitroxazepine, nortriptyline, noxiptiline, pipofezine, propizepine, protriptyline, and quinupramine. Monoamine oxidase inhibitors (MAOI) include phenelzine, tranylcypromine. [0041] Anti-psychotics include dopamine receptor antagonists which antagonize dopamine (and serotonin). Examples of D2 and D2/D3 antagonists include first generation anti- psychotics (typical anti-psychotics) and second generation antipsychotics (atypical antipsychotics). Pimozide is also a dopamine receptor antagonist. Other dopamine receptor antagonists include amisulpride (D2/D3 antagonist), nemonapride, remoxipride (D2 antagonist), sultropride and Iriapride as well as pharmacologically acceptable derivatives, analogs, homologs, salts and formulated forms thereof and any typical or atypical antipsychotics with full or partial dopamine antagonist actions.

[0042] Other dopamine antagonists include (5,6-dimethoxyindan-2-yl)dipropylamine; 1 -methyl- 1 ,2,3,4-tetrahydroisoquinoline; 1 -methyl-4-(2'-methylphenyl)- 1 ,2,3,6- tetrahydropyridine; 3-((4-(4-chlorophenyl)piperazin-l -yl)methyl)-l H-pyrrolo(2,3- b)pyridine; 3-iodo-2-hydroxy-6-methoxy-N-((l-ethyl-2-pyrrolidinyl)methyl)benzamide; 5- methoxy-l -methyl-2-(n-propylamino)tetralin; 8-iodo-2,3,4,5-tetrahydro-3-methyl-5- phenyl-l H^:3-benzazepine-7-ol; acepromazine; amoxapine; azaperone; benperidol; bromopride; butaclamol; chlorpromazine; chlorprothixene; clopenthixol; domperidone; droperidol; EEDQ; eticlopride: FLB 457; flupenthixol; flupenthixol decanoate; fluphenazine; lluspirilene; haloperidol; loxapine; mesoridazine; methotrimeprazine; metoclopramide; nafadotride; nemonapride; penfluridol; perazine; e henazine; pimozide; prochlorperazine; promazine; raclopride; remoxipride; risperidone; Sch 39166; SK^A&F 83566; spiperone; spiroxatrine; stepholidine; sulpiride; sultopride; tetrahydropalmatine; thiethylperazine; thioridazine; thiothixene; tiapride; trifluoperazine; trifluperidol; triflupromazine; UH 232; ziprasidone; dopamine uptake inhibitors may also be used which include (l R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; 1 -(2-(diphenylmethoxy)ethyl)-4- (3-phenyl-2-propenyl)piperazine; amphetamine; benzphetamine; benztropine; bupropion; cocaethylene; cocaine; dextroamphetamine; duloxetine; mazindol; methamphetamine; methylphenidate; nomifensine; and vanoxerine.

[0043} Reference to mood stabilizers includes inter alia antimania, anticonvulsants, antipsychotics and antihypertensives. Examples includ lithium carbonate, divalproex sodium, tiagabine, levetiracetam, lamotrigine, gabapentin, carbamazepine, oxcarbazepine, topiramate, zonisamide, olanzapine, verapamil, clonidine, propranolol, mexiletine and guanfacine.

[0044] Naturally occurring synthetic modified, and steroidal and non-steroidal forms of estrogens as well as plant-like compounds which induce estrogens, and estrogen pro-drugs are contemplated for use in accordance with the present disclosure. Examples include 2,3- bis(3'-hydroxybenzyl)butane-l,4-diol; 2,3-bis(3'-hydroxybenzyl)butyrolactone; 4- octylphenol; 8-prenylnaringenin; biochanin; bisphenol A; chlorotrianisene; coumestrol; daidzein; dienestrol; diethylstilbestrol; diethylstilbestrol dipropionate; cpimestrol; equol; estradiol; estrogenic steroids, alkylated; estrogens, conjugated (USP); phytoestrogens; estrogens, conjugated synthetic A; estrogens, conjugated synthetic B; estrogens, esterified (USP); estrone; ethinyl estradiol; formononetin; genistein; glycitein; hexestrol; infecundin; mestranol; ο,ρ'-DDT; polyestradiol phosphate; quinestrol; secoisolariciresinol; zearalenone and zeranol. Selective estrogen receptor modulators (SERMs) include: clomifene, femerelle, ormeloxifene. raloxifene, tamoxifen and toremifene. An example of an estrogen pro-drug is tibolone or a pharmaceutically acceptable salt or functional equivalent thereof.

[0045] The present disclosure enables the use of any naturally occurring, synthetic and chemically modified progestogens as well as their functional equivalents including plant progesterone-like compounds. The present disclosure also includes any compounds which induce a naturally occurring progestogen or which are metabolized into a functional progestogen, or slow release progestogen patches and implants. Examples include but are not . limited to; P5 P4 (pregn-4-ene-3,20-dione); 17-hydroxyprogesterone or 17- Hydroxypregn-4-ene-3,20-dione; pregnenalone; cholesterol; lepidium meyenii; dihydroprogesterone; 17-acetyl-lO, 13 -dimethyl- 1 ,2 ,8, 9,1 1 ,12,14,15, 16, 17- decahydrocyclopenta[a] phenanthren- 3-one; 6,17-dimethylpregna-4,6-diene-3,20-dione; androstenedione; progestin; progestogenic steroids; progesterone (USP); dienogest; dydrogesterone; medrogestone; medroxyprogesterone acetate; drospirenone; ormiloxifene. [0046] The drugs may be simultaneously or sequentially administered. Hence, the drugs may be provided in a single formulation or in a multipart form in which the contents are admixed prior to the administration. Where sequential administration occurs, the drugs may be provided within nanoseconds, milliseconds, seconds, a minute or minutes, hours or days apart. The present disclosure further teaches a therapeutic or medicament kit comprising two or more drugs selected from: (i) an HPA-axis normalizing agent selected from oxytocin or an agonist thereof, a CRH or CRH receptor antagonist, a AVP antagonist, a ACTH antagonist, a glucocorticoid antagonist, and a dopamine antagonist; (ii) an SSRI, SSNRI or other anti-depressant (iii) anti-psychotic; and optionally (iv) an estrogen, estrogen analog or estrogen agonist or SERM, estrogen pro-drug and or (iv) a progestogen or progestogen analog or agonist. In an embodiment, the formulation comprises oxytocin and estrogen. In another embodiment, the disclosure comprises oxytocin, estrogen and an anti-depressant such as selected from an SSRI, SSNRI, a tri-cyclic anti-depressant and a tetra-cyclic anti-depressant.

(0047] The formulations may also be in a form requiring reconstitution or admixing with a pharmaceutically acceptable carrier, diluent or excipient prior to use.

[0048] The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. [0049] Pharmaceutical compositions taught therein suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredien with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound- moistened with an inert liquid diluent.

[0050] The drugs taught herein may be administered orally, parenterally (including by subcutaneous, intravenous, intra-arterial, intramuscular, intrasternal, intra-peritoneal injection or infusion techniques), topically such as via ophthalmic and mucus membranes, by inhalation, by intranasal spray, or rectally, in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, excipients, diluents and/or other vehicles. [0051] Pharmaceutical compositions and formulations for topical administration include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders,

[0052] When administered by nasal aerosol or inhalation, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.

[0053) Intravenous administration includes both bolus and infusion when administered by injection, the injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.

[0054] When rectal ly administered in the form of suppositories, these compositions may be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter, synthetic glyeeride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.

[0055] The effective dosage of the agents employed in therapy may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Thus, the dosage regimen utilizing the compounds of the present disclosure is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the rerial and hepatic function of the patient; and the particular compound thereof employed. A physician or clinician of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition. Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.

[0056] Optimal dosing schedules can be calculated from measurements of drug accumulation in the body of the patient. Persons of ordinary skill can easily determine optimum dosages, dosing methodologies and repetition rates. Optimum dosages may vary depending on the relative potency of individual agents, and can generally be estimated based on EC50S found to be effective in in vitro and in vivo animal models. In general, dosage is from 0.01 μg to 100 g per kg of body weight, and may be given once or more daily, weekly, monthly or six monthly or as required. Persons of ordinary skill in the art can readily estimate repetition rates for dosing based on measured residence times and concentrations of the drug in bodily fluids or tissues. Variations may include daily, twice daily, thrice daily, weekly, multiple weekly and dosage may include a range of 1 - 1 ,000 international units (IUs). Following successful treatment, it may be desirable to have the patient undergo maintenance therapy to prevent the recurrence of the disease state, wherein the drugs are administered in maintenance doses, ranging from 0.01 μg to 100 g per kg of body weight, once or more daily, weekly, monthly, six monthly or as required. Variations may include daily, twice daily, thrice daily, weekly, multiple weekly and dosage may include a range of 1 - 1 ,000 international units (IUs). [0057] The pharmaceutical formulations enabled herein, which may conveniently be presented in unit dosage form, may be prepared according to conventional techniques well known in the pharmaceutical industry. Such techniques include the step of bringing into association the active ingredients with the pharmaceutical carrier(s) or excipient(s). In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

[0058] The compositions described herein may be formulated into any of many possible dosage forms such as, but not limited to, tablets, capsules, gel capsules, liquid syrups, soft gels, suppositories, and enemas. The compositions herein described may also be formulated as suspensions in aqueous, non-aqueous or mixed media Aqueous suspensions may further contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and/or dextran. The suspension may also contain stabilizers. (0059] The drugs proposed to be used in accordance with the subject method may also be referred to as medicaments, agents, therapeutics, actives, vaccines, compounds and the like. Reference to a "medicament", "agent", "therapeutic", "active", "vaccine" and "compound" includes a single drug or a combination of two or more drugs. The drugs may also be referred to as neuropsychopharmacological^'agents. This term is not to exclude agents which modulate signaling targets within the stress-linked biological system or reproductive linked system.

[0060] The subject contemplated herein is generally a human subject and may also be referred to as a patient, individual or recipient. The human subject may be an infant, child, adolescent, teenager, young adult, adult or elderly adult of male or female gender. Notwithstanding, the present disclosure extends to the use of the drug combinations in a variety of small to large animal models such as mice, rats, guinea pigs, hamsters, cats, dogs, pigs, sheep, cattle, horses, camels, monkeys and other non-human primates. One useful animal model is the Forced Swim Test (or Porsolt Test). This model is useful inter alia for testing drug combinations for acute and chronic conditions.

[0061] The present disclosure further enables a combination of drugs selected from: (i) an HPA-axis normalizing agent selected from oxytocin or an agonist thereof, a CRH or CRH receptor antagonist, a AVP antagonist, a ACTH antagonist, a glucocorticoid antagonist, an anti-psychotic and a dopamine antagonist; (ii) an SSRI, SSNRI or other anti-depressant; (iii) a mood stabilizer and optionally (iv) an estrogen, estrogen analog or estrogen agonist or SERM or estrogen pro-drug, and/or (v) progestogen, progestogen analog, progestogen agonist in the manufacture of a medicament for the treatment or prophylaxis of a psychological illness.

[0062] The present disclosure further describes a vaccine for use in the treatment of chronic conditions. In particular, a vaccine is contemplated which induces antibodies against a particular HPA axis target, e.g, CRH as an antigen to generate antibodies specific for CRH or ACTH as an antigen to generate ACTH-specific antibodies. A range of other HPA axis components may be used in a vaccine formulation. The present disclosure further contemplates active and passive immunization protocols. Hence, the term "vaccine" or "vaccine formulation" includes a preparation of antigens to induce a humoral (antibody) response as well as preparation of antibodies for use in passive immunization. Antigens may need to be conjugated to a larger foreign molecule such as keyhole impact hemocyanin (KLH) or bovine serum albumin (BSA). The complex (including the immunization target) is usually administered to the subject as a primary injection, followed by one or more booster injections, as required for treatment and maintenance. For antibody formulations, antibodies are contemplated from any source such as humans, horses, goats, sheep, pigs, etc. Non-human antibodies are generally de-immunized or humanized for use in human patients. Immunoglobulin-like molecules from marine vertebrate animals such as sharks and rays may also be employed. One particular type is a shark -derived antibody referred to as an "IgNAR" (immunoglobulin new antigen receptor). This approach may be useful for the treatment of acute symptoms (and the effect can be reversed or controlled) and may also be used in the early stages of treatment, to accelerate the impact of other agents used in the method of treatment.

[0063] By "treatment" includes aspects of prevention (prophylaxis) such as in subjects at risk of developing a psychological condition. Such as genetically or environmentally predisposed individuals.

[0064] Aspects of the subject method are further described by the following non-limiting Examples. These Examples take the form of an empirical review of the literature culminating in the selection of the combinations of drugs proposed to be useful in accordance with the subject method. EXAMPLE 1

Major depression and the hypothalamopituitary adrenal (HPA)-axis

[0065] When experiencing a stressor that is real (or perceived) [Tilbrook and Clarke, Front Neuroendocrinal 27^:285-307, 2006], the HPA-axis is activated. The hypothalamus secretes corticotropin-releasing hormone (CRM) and arginine vasopressin, AVP, which act on the pituitary to stimulate and secrete adrenocorticotrpin hormone (ACTH), and finally, ACTH binds receptors in the adrenal glands to stimulate the secretion of Cortisol, An important component of this normal stress response is the capacity to appropriately cease (abrogate) it, once the stressor has passed. Where activity of the HPA-axis is not appropriately regulated, disorders linked to chronic and excessive activation of the stress system occur, which include MDD (Gold and Chrousos, 2002 supra; Tilbrook and Clarke, 2006 supra). [0066] Gold and Chrousos, 2002 supra amongst others (Parker et ai, Horm Behav 43(l):6Q-66, 2003) have established the concept of different physiological states to describe activity of the HPA-axis relevant to MDD. Patients are characterized as having hyper- (overactivity) or hypo-(under) activity of the HPA-axis (Gold and Chrousos, 2002 supra). Hyperactivity of the HPA-axis response to stress in MDD (Juruena et a!., 2009 supra) is illustrated via increased levels of Cortisol in saliva, plasma and urine and increased size (and activity and responsivity) of the pituitary and adrenal glands (Nemeroff and Vale, 2005 supra). Normalization of the HPA-axis is required for a response to antidepressant treatment in some patients (Binder et ai, 2009 supra. Young et ai, 2004 supra; Juruena et ai, 2009 supra) therefore, the HPA-axis in MDD is an important target to understand in relation to anti-depressant treatment response. EXAMPLE 2

Overactivity of the HPA-axis is a mechanism preventing response to anti-depressants

[0067] Hyperactivity of the HPA-axis prevents a response to anti-depressant treatment in some patients (Binder et al, 2009 supra, Young et al, 2004 supra; Juruena et al, 2009 supra). This is supported by evidence that in an inpatient setting, individuals (Young et al., 2004 supra; Juruena et al, 2009 supra) who subsequently failed to respond to two antidepressant interventions (including SSRIs) showed elevated HPA-axis activity at baseline, failed to normalize at treatment follow-up (Young et al, 2004 supra; Juruena et al, 2009 supra). Furthermore in some patients (versus healthy controls) excessive concentrations of ACTH were reported (Young et al, 2004 supra).

[0068] The relationship between activity of the HPA-axis, serotonin modulators and stress- modulators, can be extrapolated from Abumaria et al, Eur Neuropsychopharmacol 17(6- 7^:417-429, 2007 and Yanpallewar et al, J Neurosci 30(3):l 096- 1 109, 2010 which show that excessive activation of the HPA-axis leads to a reduction of serotonin levels by increasing the enzyme that breaks down serotonin (tryptophan hydroxylase) [Abumaria et al, 2007 supra]. This can be reversed with SSRI (citalopram) treatment (Abumaria et al, 2007 supra). In addition to which, treating depression (in an animal model) with co- administration of stress-reducing drugs (ct2-adrenoceptor inhibitor) and anti-depressants (imipramine), results in a more rapid and accelerated reduction in depressive symptoms (physiological [Bessa et al, Mol Psychiatry J 4(8) 764-773, 2009] and behavioral) in 7 days compared with 21 days seen in animals treated with anti -depressants alone (Yanpallewar et al, 2010 supra; Bodo, Nature Reviews NeuroscienceA l , 2010). Translated to MDD, these outcomes provide further rationale for targeting the HPA-axis in those with TRD. CRH (Gold and Chrousos, 2002 supra) and ACTH (Young et al, 2004 supra) are commonly reported mechanisms for overactivity of the HPA-axis in MDD. Hence, treatments reducing CRH or ACTH levels may enable a response to antidepressants. EXAMPLE 3

Use of oxytocin

[0069] Oxytocin is a neuropeptide with a wide spectrum of actions in the brain and body (Heinrichs and Domes, Prog Brain Res 770:337-350, 2008). Oxytocin binds significantly in the hypothalamus (see Figure 1) and the limbic system, including the amygdale (Huber et al. Science 308(571 \9) :245-248, 2005; Ingram et al., J Neuroendocrinal 7(7j: l -13, 1995; Landgraf and Neumann, Front Neuroendocrinal 25(3-4): 150-176, 2004; Raggenbass, Prog Neurohiol 64(3):307-326, 2001) linked to oxytocins functional role in reducing stress and anxiety across species (Bale et al, J Neurosci 27^:2546-2552, 2001 ; Cater et al., J Anxiety Disord 75^:555-569, 2001 ; Neumann et al., Neuroscience 95 /2j:567-575, 2000; Parker el al., Psychoneuroendocrinology 30(9):924-929, 2005; Windle et al., J Neurosci 24(/2):2974-2982, 2004; Heinrichs et al, Front Neuroendocrinal 30(^:548-557, 2009) amongst other functions. Oxytocin in an intranasal form (enabling its effects on the central nervous system to be determined), has been shown in several randomized controlled trials (RCTs) to effectively treat symptoms in social phobia and autism spectrum disorder (Guastella et al, Psychoneuroendocrinology 34(6):9\7-923, 2009; Guastella el al, Biol Psychiatry, 2009; Andari et al, Proc of the Nat Acad of Sci; 2010). [0070] In MDD, studies have shown that reduced plasma oxytocin concentrations are associated with increased depressive^' symptom severity (Ozsoy et al, Psychiatry Res J69(3):249-252, 2009; Anderberg and Uvans-Moberg, Z Rheumatol 59(^:373-379, 2000) and anxiety ((Frasch et al, Adv Exp Med Biol 3.95:257-258, 1995). These data show a significant deficit in oxytocin linked to depressive symptoms in patients with MDD.

[0071] Other studies demonstrate reduced plasma oxytocin levels in depressed patients (Frasch et al, 1995 supra) and reduced serum oxytocin concentrations before and after treatment (compared with healthy controls) suggesting oxytocin may present a trait (enduring) marker for MDD (Raggenbass, 2001 supra; Ozsoy et al, 2009 supra). [0072] Oxytocin significantly reduces activity of the HPAr-axis (Parker et al., 2005 supra; Windle et al., Endocrinology /5S( ):2829-2834, 1997). Furthermore, intranasal oxytocin attenuates the stress (e.g. ACTH) response in monkeys (Parker et al., 2005 siipra). [0073] In the context of patients with TRD then, where it is reported that patients who fail to respond to antidepressants demonstrate overactivity of the HPA axis, it is plausible that overactivity of the HPA-axis in some patients (Young et al., 2004 supra; Juruena et al., 2009 supra) may be due in part to reduced oxytocin concentrations.

EXAMPLE 4

Use of CRH antagonists

(0074] Reducing CRH stimulation and secretion can reduce activity of the HPA-axis. Consistent with evidence that CRH is abnormally overactive in patients with MDD (gold and Chrousos, 2002 supra), a number of studies have demonstrated the positive effects of drugs that reduce the secretion of CRH (via blocking the CRHl receptor) in patients with MDD. In a preliminary monotherapy study a selective antagonist of CRHl (R 121919) reduced Hamilton depression score ratings (HAM-D) in 20 patients with MDD(HAM-D) [Zobel et al, J Psychiatr Res 34(3): Π3-\ Π, 2005]. Importantly, the drug showed no impact on weight gain or plasma leptin concentrations (Kunzel et al, J Psychiatr Res 39(2): \Τ3-\Π , 2005), gonadal and rennin-angiotensisn systems, prolactin or arginine vasopressin secretion (Kunzel et al., J Psychiatr Res 37 (6) :525-533, 2003). A 30-day dose- escalatjon trial (e.g., 5-40mg or 40-80mg) further confirmed that the drug is safe, efficacious and well tolerated (Zobel et al,, 2000 supra). Furthermore, the drug does not preclude a normal response of the HPA-axis to stressor challenges (Kunzel et al., 2003 supra) but reduces baseline (or resting) HPA-axis hormone concentrations (Kunzel et al., 2003 supra). Other studies have not shown an impact of CRHl antagonism on symptoms of MDD (Binneman et al., Am J Psychiatry 165(5):617-620, 2008) although a different CRHl angatonist was employed (CP-316,31 1). Owing to its demonstrated clinical effect in MDD (Zobel et al., 2000 supra; Kunzel et a!., 2003 supra) the potential for positive effects of CRH modulation, which have not been investigated in TRD, warrant testing.

[0075] Hence, resistance to anti-depressant treatment can be predicted by overactivity of the HPA-axis (Juruena et al., 2009 supra). To address this clinical problem, it is proposed herein to induce inhibitio of HPA-axis activity by either; increasing oxytocin concentrations, or reducing CRH, AVP or ACTH levels. EXAMPLE 5

Use of Estrogens to reduce activity of the HPA axis

[0076] Estrogen can reduce activity of the HPA axis in the context of stress in females {Young et al, Psychoneuroendocrinology. 29(9): 1198-1204, 2004). Using estrogen antagonists (tamoxifen and CI 628), Young et al, 2004 supra demonstrated an increase in ACTH and corticosterone response to restraint stress in female rats. Conversely, in ovariectomized female rats, low dose estradiol (over 7 days) decreased ACTH response to stress (Young et al, 2004 supra).

[0077] Estrogen has not been used to manage treatment resistant depression, however, it is proposed herein to induce inhibition of the HPA axis via its interactions with oxytocin. For example, there is clear evidence for a direct relationship between estrogen and oxytocin in the hypothalamic subdivision of the HPA axis, which places well, for an interaction between oxytocin and estrogen to explain their effects on the HPA axis. In rats, in distinct sub-regions 45-98% of the hypothalamus oxytocin neurons have been shown to exhibit oestrogen-receptor (ERP) immunoreactivity (confined to cell nuclei) [Hrabovszky et al,. J Comp Neurol. 473(3):3 l 5-333: 2004]. In addition, double-label immunocytochemical analysis of human autopsy samples showed that subsets of OT (and VP) neurons also express ΕΡ%.β.

EXAMPLE 6

Double-blind randomized trial of hormone (adjunct) therapies in treatment resistant depression [0078 j The aim is to compare the efficacy and safety of a combined therapeutic protocol, combined agents which normalize HPA-axis activity with an SSRI, escitalopram, in treating symptoms of depression in patients with TRD. That is, patients who have not previously responded to at least two interventions, including SSRI therapy. Escitalopram is chosen due to its highly specific and selective actions on the serotonin system.

[0079] Specific aims include:

1. Determining the influence of increasing oxytocin on characteristics of TRD.

2. Determining the influence of reducing CRH on characteristics of TRD.

3. Elucidate abnormalities in HPA-axis mechanisms in patients with TRD before and after treatment.

[0080] It is proposed that patients with TRD have overactivity of the HPA-axis and reduction of this activity is proposed to enable a therapeutic response to SSRI treatment. It is further proposed to show improvement in depressive symptoms as measured by MADRS scores which is greater in each of the two active adjunct (hormone) groups compared to the non-active placebo adjunct group. In addition, relative to baseline, it is proposed that there is a greater reduction in HPA-axis activity following hormone (active treatment) relative to placebo (non-active) adjuncts as measured by endocrine levels and perceived stress-scale.

[0081] This example has been designed consistent with the CONSORT guidelines. This is a three-ann double-blinded parallel-group randomized pilot trial to compare the efficacy and safety of 3 different escitalopram adjuncts in patients with MDD that have previously not shown a clinical response to escitalopram (or other SSRI and at least one other intervention). All patients will take the SSRI, escitalopram, and a comparison made on the efficacy and safety of: oxytocin adjunct (Syntocinon or other commercially or non- commercially available alternative/homolog) or corticotropin releasing hormone (CRH) adjunct (561679 or other commercially or non-commercially available alternative/homolog) to placebo adjunct. The use of two hormone adjuncts plus a placebo adjunct is a design that allows investigation of the efficacy of three different adjuncts and determine whether novel hormones (oxytocin agonist and CRH antagonist) result in better efficacy than escitalopram and the endocrine mechanisms contributing to this outcome. A clinical improvement would suggest improvement over the effects of escitalopram alone. A pilot trial comparing the efficacy of the adjunct approaches would, therefore, enable the most efficient approach (or both approaches) to be further phased through larger more definitive clinical trials. With 40 patients in each arm:

Group 1 : escitalopram + oxytocin agonist (syntocinon);

Group 2: escitalopram + CRH antagonist (561679);

Group 3: escitalopram + placebo. [0082] Participants are patients that have failed to progress clinically on an SSRI (and at least one other intervention) despite an adequate duration and highest tolerated dose (Berlim and Turecki, 2007 supra; Souery et al, Eur Neuropsychopharmacol 9(102):S3-9\ , 1999) of an SSRI (e.g., any SSRI, such as escitalopram, fluoxetine, paroxetine). Following screening, patients already prescribed escitalopram (for at least 4 weeks at the highest tolerated dose) enter the double-blind phase of the trial. For those requiring a washout for 1-2 weeks (depending on drug interactions) the double-blind phase will begin following 4 weeks of monotherapy with escitalopram. Baseline measures are then be completed and patients are randomly allocated to an investigational group (1 , 2 or 3). Patient visits tocollect blood samples and assess changes in clinical symptoms and the HPA-axis will occur at day 28, 56, 84 (ie., every 4 weeks until the trial end-date).

Treatment Schedule

[0083] Group 1: Oxytocin are intranasally administered at a total dose of 24 IU (international units) (40.32 g). 12 IU will be sprayed into each nostril (three puffs per nostril each with 4 IU oxytocin) each day consistent with established efficacy and tolerability in patients with social phobia (Guastella et al., 2009 supra). SSRl dosing design will be the maximum prescribed dose of escitalopram (20mg).

[0084] Group 2: CRH (561679 Glaxosmithkline or alternative) are orally administered at a dose of 80mg consistent with manufactures established efficacy and safety in patient trials. SSRl dosing design will be the maximum prescribed dose of escitalopram (20mg).

[0085] Group 3: Placebo (vehicle) are both intranasally administered in spray form in some patients or orally administered in tablet form in other patients to present appropriate non-active^' treatment controls for oxytocin (instranasal spray) and CRH (orally administered tablet). SSRl dosing design is the maximum prescribed dose of escitalopram (20mg).

Inclusion criteria:

· 18-45 years and a current DSM-IV diagnosis of major depression.

• Past treatment failure to at least 2 anti-depressants including an SSRl, at the highest tolerated dose for at least 4 weeks.

• A MADRS score >20

• Co-morbid panic or anxiety disorders secondary to depression are included.

Exclusion criteria:

• Any previous history of adverse side-effects to escitalopram (or other SSRl).

• DSM-IV defined substance dependence, intellectual disability or significant unstable medical illness including epilepsy, diabetes or cardiac related, renal or liver disease or pregnancy.

[0086J Screening: Patients are screened as soon after referral as possible. Once informed consent is obtained, procedures for the study begin. Patients undergo full psychiatric and medical history examination and non-invasive physical examination. Psychopathology is assessed, to confirm symptom severity and history of failed treatment response. A blood sample is taken in females to confirm hormone profiles, confirm stage of menstrual cycle and pregnancy status.

(0087] Randomization procedure: Following receipt of consent to participate, each participant is allocated an identification number, and randomly assigned to a treatment regimen. The randomization procedure is organized using a (pseudo-randomized) code generated by computer. Equal numbers are assigned to the three treatment arms at a 1 :1 : 1 ratio, where patients, raters, clinicians and researchers are "blind" as to the active (ie., hormone) or non-active (ie., placebo) treatment a patient receives.

[0088] Baseline visit: Medication is dispensed at baseline, following confirmation by pathology reports (from blood taken at screening visit) that patients meet inclusion criteria. Other procedures performed include: psychopathology and collection of blood for endocrine/hormone assays as well as 24 hour salivary Cortisol tests.

[0089] Evaluation visits: At evaluation visits, the researchers record adherence, adverse events and administer psychopathology rating scales and collect blood for hormone assays. A 10 ml blood sample is taken at each study visit to measure: Oxytocin, CRH, ACTI l, Cortisol, DHEA, progesterone, prolactin, FSH, LH, estrogen, testosterone.

Instruments for data collection

[0090] Diagnostic: The MINI International Neuropsychiatric Interview (MINI) [Sheehan et al, J Clin Psychiatry 59(20):34-57, 1998] is used to confirm diagnosis for patients entering the study. The MINI is performed by a trained researcher prior to randomization.

[0091] Psychopathology:

•Hamilton Rating Scale for Depression (HAM-D) [Hamilton, Journal of Neurol, Neurosurg and Psych 25:56-62, I 960]; a 21 -item questionnaire for clinician-rated severity of major depression. •Hamilton Rating Scale for Anxiety (HAM - A) [Hamilton, Br J Med Psychol 52:50-55, 1959]: a 14 item questionnaire for clinician-rated severity of anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety)

•Beck Depression Inventory (BDI) II [Beck et al, Journal of personality assessment 6 (3) :588-597, 1996]: a 21-item questionnaire for patient self-reported severity of depression.

•CORE (Hadzi-Pavloic and Parker, Melancholia: A disorder of Movement and Mood New York: Cambridge University Press: 130-137, 1996): 18-item observer-rated scale for classification of melancholia. Assesses depression on three dimensions: retardation, agitation and non-interactiveness.

•Perceived stress scale - 10-item self report questionnaire for evaluating the stressfulness of the situations in the past month of life.

•Life events scale - Measures the amount of change, using Life Change Units, a person experienced and adjusted to in the previous 12 months.

•Pittsburgh sleep quality index (Buysse et al, Psychiatry Research 25:193-213, 1989) - self report questionnaire pertaining to usual sleep habits during the past month.

•Montgomery Asberg Depression Rating Scale (MADRS) [Montgomery and Asberg, Br J

Psychiatry 75^:382-398,. 1979]: a 10-item clinician rated scale. It is robustly sensitive to changes in depression with treatment.

[0092] Safety and Tolerance: Adverse Symptom Checklist (ASC): a 21-item scale to rate the presence and severity of (0 = not present, to 3 = severe) of common symptoms associated with psychotropic treatments. [0093] Pathology and other tests: Physical examination: weight, hip-waist measure. Serum lipids; Liver and renal function; Full blood exam (FBE); Random blood glucose. Hormone analysis in women (only) at baseline: estradiol, follicle-stimulating hormone, luteinizing hormone, prolactin, dehydroepiandrosterone (DHEA), progesterone, prolactin, human chorionic gonadotropin hormone (HCG) to determine menstrual status/pregnancy status. (0094] Medications: Medication is dispensed following screening (and pathology tests) at baseline, and each four-weekly study visit thereafter. The prescription is filled according to the randomization relevant to each participant, which will then be collected by the study co-ordinator and given to the participant at each visit.

{0095] Concomitant treatments: All patients engage in their routine psychosocial therapies as advised by their treating physician. All medication received during the study (psycho-tropic and non-psychotropic) will be recorded. No other concomitant psychotropic medications is permitted..

[0096] Sample size: The primary end point for the current study is change from baseline MADRS score at week 12. A difference of at least 8 points between the treatment and placebo groups on the mean change in MADRS score is considered clinically significant. Assuming a standard deviation of 10 points (conservative estimate from previous trials) and a power of 90% (alpha = 5%). 99 participants are required across the three groups. Considering a withdrawal and non-compliance rate of 15%, a total sample of 120 (40 per group) are recruited.

[0097] Statistical Analysis: All data are analyzed using SAS version 9.1 (SAS Institute Inc, Cary, NC, USA). Analysis will be performed on participants who complete 1 ) at least one post-baseline treatment visit (intention to treat) and 2) per protocol to provide a measure of reliability of the primary analysis. Data are assessed for normality and log- transformed where appropriate. Univariate analysis is conducted using chi-square test for equal proportion, analysis of variance and non-parametric Kruskal-wallis tests where required. The primary efficacy measure is the change from baseline to the end of treatment in MADRS score. Primary inferential analysis is conducted using a mixed effects model for the intention to treat population. This model includes treatment as a fixed effect with other clinical and demographic factors as potential covariates. A two-sided p-value of 0.05 will be considered statistically significant. EXAMPLE 7

Double-blind randomized trial of hormone (adjunct) therapies in treatment resistant depression [0098] The aim of this project is to test a novel method of treating patients with Treatment Resistant Depression (TRD) by targeting the physiological stress system or hypothalamopituitary adrenal (HP A) axis. The aim is to compare the efficacy and safety of a combined therapeutic protocol, combined agents which normalize HPA-axis activity with an SSR1, escitalopram, in treating symptoms of depression in patients with TRD. That is, patients who have not previously responded to at least two interventions, including SSRI therapy. Escitalopram is chosen due to its highly specific and selective actions on the serotonin system.

[0099] Specific aims include:

1. Determining the influence of increasing oxytocin on characteristics of TRD.

2. Determining the influence of increasing oxytocin and tibolone on characteristics of TRD.

3. Elucidate abnormalities in HPA-axis mechanisms in patients with TRD before and after treatment.

[0100] It is proposed that patients with TRD have overactivity of the HPA-axis and reduction of this activity is proposed to enable a therapeutic response to SSRI treatment. It is further proposed to show improvement in depressive symptoms as measured by MADRS scores which is greater in each of the two active adjunct (hormone) groups compared to the non-active placebo adjunct group. In addition, relative to baseline, it is proposed that there is a greater reduction in HPA-axis activity following hormone (active treatment) relative to placebo (non-active) adjuncts as measured by endocrine levels and perceived stress-scale. [01.01] This clinical trial is designed consistent with the CONSORT guidelines. This is a three-arm double-blinded parallel-group randomized pilot trial. All patients are female and take the SSRI, escitalopram, and the efficacy and safety of active adjuncts oxytocin (syntocinon intranasal spray) and tibolone (orally) to non-active adjunct placebo are compared. The use of two active adjuncts and a non-active placebo adjunct is a design that allows investigation of whether novel hormone oxytocin, or oxytocin and tibolone result in better efficacy than placebo in TRD. The endocrine mechanisms contributing to treatment outcomes are systematically studied. The trial Is 12 weeks. A total of 90 patients are recruited and randomly allocated to one of the following groups in a 1 :1 : 1 ratio with 30 patients in each arm: Group 1 : escitalopram + oxytocin (syntocinon intranasal spray) + tibolone

Group 2: escitalopram + oxytocin (syntocinon intranasal spray) + placebo

Group 3: escitalopram + placebo (intranasal spray) + placebo (oral)

[0102] Participants are patients that have failed to progress clinically on an SSRI (and at least One other intervention) despite an adequate duration and highest tolerated dose (Berlim and Turecki, 2007 supra; Souery et al, Eur Neuropsychopharmacol 9(102):83-9] , 1999) of an SSRI (e.g., any SSRI, such as escitalopram, fluoxetine, paroxetine). Following screening, patients will undergo a drug washout for 1-2 weeks (depending on drug interactions) if medication is being taken. Baseline measures will then be completed and patients will be randomly allocated to an investigational group. Patient visits to collect blood samples and assess changes in clinical symptoms and the HPA axis will occur at: baseline, day 14, 28, 56, 84 (ie., baseline, week 2 and then every 4 weeks).

Treatment Schedule

[0103] Group 1: Oxytocin will be intranasally administered at a total dose of 24 IU (international units) (40.32μg). 12 IU will be sprayed into each nostril (three puffs per nostril each with 4 IU oxytocin) each day consistent with established efficacy and tolerability in patients with social phobia. Escitalopram dosing design will be standard. Patients receive daily oral tibolone 2.5mg/day (dose approved by the TGA for postmenopausal women). [0104] Group 2: Oxytocin is intranasally administered as described above. Escitalopram dosing design is standard. A daily oral placebo (vehicle for tibolone) is administered.

[0105] Group 3: Escitalopram dosing design is standard. Intranasal placebo (vehicle for oxytocin) is administered and daily oral placebo (for tibolone) is administered.

[0106] Protocols: Aspects including exclusion criteria, inclusion criteria, screening, randomization procedure, baseline visit, evaluation visits, instruments for data collection, diagnostic and psychopathology, safety and tolerance, pathology and other tests, medications and concomitant treatments are as per Example 5.

[0107] Sample size: The primary end point for the current study is change from baseline MADRS score at week 12. A difference of at least 8 points between the treatment and placebo groups on the mean change in MADRS score is considered clinically significant. Assuming a standard deviation of 10 points (conservative estimate from previous lrials75) and a power of 80% (alpha = 5%), 75 participants are required across the three groups. Considering a withdrawal and non-compliance rate of 15%, a total sample of 90 (30 per group) will be recruited. [0108] Statistical Analysis: All data are analyzed using SAS version 9.2 (SAS Institute Inc, Cary, NC, USA). Analysis is performed on participants who complete 1) at least one post-baseline treatment visit at week 4 (intention to treat) and 2) per protocol to provide a measure of reliability of the primary analysis. Data are assessed for normality and log- transformed where appropriate. Univariate analysis will be conducted using chi-square test for equal proportion, analysis of variance and non-parametric Kruskal-wallis tests where required. The primary efficacy measure Is the change from baseline to the end of treatment in MADRS score. Primary inferential analysis is conducted using a mixed effects model for the intention to treat population. This model includes treatment as a fixed effect with other clinical and demographic factors as potential covariates. A two sided p-value of 0.05 is considered statistically significant. EXAMPLE 8

Treatment of depression

[0109] In this example, subjects are treated as follows:

(i) Oxytocin + estrogen;

(ii) Oxytocin + estrogen + an anti-depressant.

(0110] Methodologies are as per Examples 6 and 7. [011.1] The anti-depressants are selected from an SSRI, SSNRI, a tri-cyclic anti-depressant and a tetra-cyclic anti-depressant. Examples of an SSRI include escitalopram, sertraline, citalopram, fluoxetine and agomelatine. Examples of an SSNRI include esmertazapine, venlafaxine, desvenlafaxine and duloxetine. Examples of a tri-cyclic anti-depressant include amitriptyline and imipramine. Examples of a tetracyclic anti-depressant include amoxapine and mirtazapine.

[0112] Candidates have symptoms of depression. Some have treatment resistant depression. The drugs are given separately or as part of a single or multiple formulation. In preparation for the treatment of human patients, an animal model may be used. An example of a suitable animal model is the Forced Swim Test (or Porsolt Test). Such an animal model is particularly useful in testing drugs in acute and chronic treatments.

[0113] Those skilled in the art will appreciate that the embodiments described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the various embodiments include all such variations and modifications. The subject method also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of the steps or features. BIBLIOGRAPHY

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Claims

CLAIMS:

1. A method of treating a human subject diagnosed with symptoms of depression, said method comprising administering to said subject effective amounts of oxytocin and estrogen for a time and under conditions sufficient for the symptoms of depression to be ameliorated.

2. The method of Claim 1 further comprising administering an effective amount of an anti-depressant selected from a selective serotonin re-uptake inhibitor (SSRI), a selective serotonin and noradrenergic re-uptake inhibitor (SSNRl), a tri-cyclic anti-depressant and a tetra-cyclic anti-depressant.

3. The method of Claim 2 wherein the SSRI is selected from escitalopram, sertraline, citalopram, fluoxetine and agomelatine.

4. The method of Claim 2 wherein the SSNRI is selected from esmirtazapine, venlafaxine, desvenlafaxine and duloxetrine.

5. The method of Claim 2 wherein the tri-Cyclic anti-depressant is selected from amitriptyline and imipramine.

6. The method of Claim 2 wherein the tetra-cyclic anti-depressant is selected from amoxapine and mirtazapine.

7. The method of Claim 1 or 2 further comprising behavioral modification therapy.

8. The method of Claim 1 or 2 wherein the depression is treatment resistant depression.

9. A pharmaceutical composition comprising a combination of an anti-depressant selected from an SSRI, SSNR1, a tri-cyclic anti-depressant and a tetra-cyclic antidepressant; estrogen and oxytocin.

10. The pharmaceutical composition of Claim 9 wherein the SSRI is selected from escitalopram, sertraline, citalopram, fluoxetine and agomelatine; the SSNRI is selected from esmirtazapine, venlafaxine, desvenlafaxine and duloxetrine; the tri-cyclic antidepressant is selected from amitriptyline and imipramine; and the tetra-cyclic antidepressant is selected from amoxapine and mirtazapine.

1 1. The pharmaceutical composition of Claim 9 or 10 further comprising a pharmaceutically acceptable carrier, diluent or excipient.

12. The pharmaceutical composition of Claim 9 or 10 or Π in the form of a sustained release or slow release formulation.

13. An agent for use in the treatment of a subject with symptoms of depression, said agent comprising oxytocin and estrogen.

14. The agent of Claim 13 further comprising an anti-depressant selected from an SSRI, an SSNRI, a tri-cyclic anti-depressant and a tetra-cyclic anti-depressant.

15. The agent of Claim 14 wherein the SSRI is selected from escitalopram, sertraline, citalopram, fluoxetine and agomelatine; the SSNRI is selected from esmirtazapine, venlafaxine, desvenlafaxine and duloxetrine; the tri-cyclic anti-depressant is selected from amitriptyline and imipramine; and the tetra-cyclic anti-depressant is selected from amoxapine and mirtazapine.

16. Use of oxytocin and estrogen in the manufacture of a medicament for the treatment of a subject with symptoms of depression.

17. Use of Claim 16 further comprising the use of an anti-depressant selected from an SSRI, an SSNRI, a tri-cyclic anti-depressant and a tetra-cyclic anti-depressant.

18. Use of Claim 17 wherein the SSRI is selected from escitalopram, sertraline, citalopram, fluoxetine and agomelatine; the SSNRI is selected from esmirtazapine, venlafaxine, desvenlafaxine and duloxetrine; the tri-cyclic anti -depressant is selected from amitriptyline and imipramine; and the tetra-cyclic anti-depressant is selected from arnoxapine and mirtazapine.